Abstract
Alzheimer’s disease (AD) is the leading cause of dementia and one of the most common causes of death worldwide. As an age-dependent multifactorial disease, the causative triggers of AD are rooted in spontaneous declines in cellular function and metabolic capacity with increases in protein stressors such as the tau protein. This multitude of age-related processes that cause neurons to change from healthy states to ones vulnerable to the damage seen in AD are difficult to simultaneously investigate and even more difficult to quantify. Here we aimed to diminish these gaps in our understanding of neuronal vulnerability in AD development by using simulation methods to theoretically quantify an array of cellular stress responses and signaling molecules. This temporally-descriptive molecular signature was produced using a novel multimethod simulation approach pioneered by our laboratory for biological research; this methodology combines hierarchical agent-based processes and continuous equation-based modeling in the same interface, all while maintaining intrinsic distributions that emulate natural biological stochasticity. The molecular signature was validated for a normal organismal aging trajectory using experimental longitudinal data from Caenorhabditis elegans and rodent studies. In addition, we have further predicted this aging molecular signature for cells impacted by the pathogenic tau protein, giving rise to distinct stress response conditions needed for cytoprotective aging. Interestingly, our simulation experiments showed that oxidative stress signaling (via daf-16 and skn-1 activities) does not substantially protect cells from all the early stressors of aging, but that it is essential in preventing a late-life degenerative cellular phenotype. Together, our simulation experiments aid in elucidating neurodegenerative triggers in the onset of AD for different genetic conditions. The long-term goal of this work is to provide more detailed diagnostic and prognostic tools for AD development and progression, and to provide more comprehensive preventative measures for this disease.
Highlights
Alzheimer’s disease (AD) has become the most prevalent agedependent neurodegenerative disorder, with over 46.8 million reported cases of AD worldwide (Cummings et al, 2016)
The simulation constructs used in this study centered around age-dependent cellular and mitochondrial oxidative signaling, similar to our previous work, the model presented here was designed with a wider array of stress responses experimentally determined to be significant to neuronal vulnerability phenotypes
The simulation results generated here highlight the importance of response pathway maintenance in degenerative aging and AD development, as evidenced by the temporal molecular signatures predicted
Summary
Alzheimer’s disease (AD) has become the most prevalent agedependent neurodegenerative disorder, with over 46.8 million reported cases of AD worldwide (Cummings et al, 2016). AD and similar age-dependent neurodegenerative diseases are characterized by severe memory impairment and widespread loss of brain function, with AD predominantly affecting neurons of the hippocampus (Moodley and Chan, 2014; Milenkovic et al, 2014). Neurodegeneration is the cumulative result of oxidative stress, tau accumulation and misfolded protein stress, inflammation, loss of mitochondrial function, impaired autophagy processes, and more (Kraemer et al, 2006; Hekimi et al, 2011; Menzies et al, 2015; Wang and Hekimi, 2015). While many cellular pathways and processes contribute to this neuronal damage, age is the strongest and most ubiquitous risk factor (Niccoli and Partridge, 2012; Guerreiro and Bras, 2015), warranting AD researchers to continually revisit the fundamentals of biological aging
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